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C. Bellantuono
Benzodiazepines andZ-Drugs During
Lactation
BetülBakay andFarukUguz
13.1 Introduction
Puerperium is an important period in women, during which the onset and exacerbation of psychiatric disorders may be observed. Anxiety disorders in this period are
frequent and affect up to 39% of women (Goodman etal. 2016). In some mothers
with anxiety disorders, the high severity of anxiety symptoms or the comorbid
depression can be very challenging. In addition, these symptoms can signicantly
interfere with the establishment of a healthy mother-infant relationship and may
have a negative impact on the future social, cognitive, and emotional development
of the child. Therefore, the mother may need medical treatment (Meades et al.
2024). Although antidepressants are rst-line drugs used in clinical practice for the
treatment of these patients, the use of benzodiazepines for a short period is not rare.
On the other hand, many postpartum women experience sleep disturbances including poor sleep quality and insomnia (Ko etal. 2012). In addition to antidepressants
and benzodiazepines, nonbenzodiazepine hypnotics (Z-drugs) are important pharmacological options in patients with insomnia (Wilt etal. 2016).
Breastfeeding is one of the major challenges in the treatment of women with
psychiatric disorders. In a retrospective study published in 2020, at least 4-week
follow-up records of 263 postpartum breastfeeding mothers were analyzed. In this
study, it was shown that continuation of breastfeeding during pharmacological treatment of mothers with depression and anxiety disorders was not associated with
serious infant problems (Uguz etal. 2020). It is well known that breast milk is the
gold standard for infant nutrition and has indispensable lifetime benets.
Breastfeeding is associated with reduced morbidity, mortality, and occurrence of
illnesses via factors including gastrointestinal mucosal maturation, decrease in the
incidence of infection, alteration in the gut microora, as well as
13
B. Bakay · F. Uguz (*)
Medical Faculty of Medicine, Department of Psychiatry, KTO Karatay University, Konya,
Turkey
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
F. Uguz, L. Orsolini (eds.), Perinatal Psychopharmacology,
https://doi.org/10.1007/978-3-031-99720-4_13
303
304
B. Bakay and F. Uguz
immunomodulatory and anti-inammatory factors, hormones, growth factors, and
cytokines (Oddy 2002; Kronenfeld etal. 2017). Therefore, pharmacological agents
that are recommended for postpartum women should be safe and not interfere with
breastfeeding as much as possible. The milk-plasma ratio (M/P) is often used to
determine the amount of drug excreted in breast milk and a ratio below 1 is preferred. However, this ratio may be misleading as it does not reect the total daily
dose received. Therefore, using the drug concentration in breast milk and the relative infant dose (RID) as a more denitive indicator would be more useful in determining exposure in breastfed infants. The RID is an indicator that estimates the
amount of drug ingested in breast milk by breastfed infants and is considered safe at
less than 10% in the literature (Eleftheriou etal. 2024). Considering that psychotropic medications may be excreted into the breast milk to at variable degrees, safety
data on psychotropic drugs during lactation is essential to minimize infant exposure
and subsequent adverse effects (Uguz and Sharma 2016).
13.2 Benzodiazepines
Benzodiazepines, especially diazepam and lorazepam, are frequently used not only
for the treatment of maternal anxiety disorders but also for the management of acute
neonatal seizures and status epilepticus in children, or as prophylactic drugs for the
management of febrile seizure in children (Kanhere 2014; Wu etal. 2016; Offringa
etal. 2017). Despite a long history of clinical usage, data so far published on the
safety of benzodiazepines in breastfeeding women are limited. However, the available scientic evidence does not demonstrate any contraindication for breastfeeding
during maternal use of these medications (Kronenfeld etal. 2017). BZDs have generally high binding to plasma proteins, high lipophilicity, and low molecular weight.
The excretion rate into milk and half-life of each BZD vary according to their differences in these parameters (Furugen etal. 2019). In general, shorter-acting agents
such as alprazolam and lorazepam are preferred to longer-acting agents such as
diazepam and clonazepam that show a high risk of accumulation in infants through
breast milk. In addition, among breastfeeding women with psychiatric diagnoses, it
is recommended a brief and intermittent usage of benzodiazepines at low doses.
Moreover, repeated doses should be avoided, if possible (Davanzo et al. 2013;
Orsolini etal. 2016; Kronenfeld etal. 2017). Table13.1 summarizes the recommendations by this paper regarding the use of benzodiazepines during breastfeeding.
It has been reported that the most commonly used benzodiazepines in the lactation period are lorazepam (52%), clonazepam (18%), and midazolam (15%) (Kelly
etal. 2012). A recent study on the pharmacological management of depression during breastfeeding, including 22 case series examining the use of BZDs and Z-drugs,
demonstrated that the RID values of alprazolam, clonazepam, diazepam, lorazepam, unitrazepam, oxazepam, zolpidem, zaleplon, and zopiclone were less than
10%, and the majority were less than 5%. In this study, among 145 newborns
exposed to BZD and Z drugs during breastfeeding, sedation and lethargy associated
with alprazolam in two infants and sedation and poor milk intake due to diazepam
13 Benzodiazepines andZ-Drugs During Lactation
305
Table 13.1
Due to its tremendous benecial effects, continuation of breastfeeding should be the main goal
in clinical practice
The available limited data suggest that there is no clear contraindication regarding the use of
benzodiazepines and Z-drugs during the lactation period
Benzodiazepines and Z-drugs should be used for a short term, with intermittent and as low
doses as possible
Shorter-acting benzodiazepines are preferred to longer-acting ones
Infants exposed to benzodiazepines via breast milk should be carefully monitored with respect
to CNS depression and feeding problems
Among benzodiazepines, lorazepam owns the largest data on safety in breastfed infants
Clonazepam should not be used during breastfeeding if it is not necessary
The best safety prole of benzodiazepines frequently used in breastfeeding women is
presented by: midazolam > lorazepam > oxazepam/alprazolam > diazepam > clonazepam
Expert recommendations based on scientic evidence and clinical experience
in one infant were demonstrated (Eleftheriou etal. 2024). Recently, data from 124
breastfeeding mothers in the Motherisk program at the Hospital of Sick Children in
Toronto, Ontario have suggested that only 1.6% of infants exposed to benzodiazepines had central nervous system (CNS) depression dened as sleepiness, poor
latching, not waking up for breastfeeding, limpness, or lack of response to stimuli.
The authors also noted that the infant sedation rate in their study was similar to that
previously reported with exposure to acetaminophen (Kelly etal. 2012). It has been
reported that adverse events such as sedation, lethargy, feeding difculties or weight
loss, drowsiness, apnea, restlessness and irritability were observed in a considerable
proportion (17–50%) of infants exposed to benzodiazepines, particularly if the
mothers used the drugs for a long period (Iqbal et al. 2002; Rubin etal. 2004;
Orsolini etal. 2016). These adverse effects are mostly resolved within two weeks
following discontinuation of the medication (Rubin etal. 2004). In addition, some
withdrawal symptoms (e.g., tremor of the extremities, diarrhea and vomiting, restlessness, inconsolable crying, irritability, growth retardation due to feeding problems, sleep disturbances, and tendency for convulsions) may be observed in infants
of women who discontinue after a long-term usage of benzodiazepines (Iqbal etal.
2002; Orsolini etal. 2016). These symptoms can appear within a few days to 3
weeks after the discontinuation and their resolution may take weeks (Iqbal etal.
2002). Therefore, benzodiazepines used for a long-term period by breastfeeding
women should not be discontinued suddenly.
13.2.1 Diazepam
Safety data of approximately 20 cases using diazepam have been published in the
literature (Rubin etal. 2004; Kelly etal. 2012; Kronenfeld etal. 2017). The available data suggest that diazepam is excreted in small amounts into breast milk
(Orsolini etal. 2016). It is usually undetectable in the plasma of most infants. Milk
to plasma ratio (M/P ratio) and relative infant dose (RID) for diazepam have been
306
B. Bakay and F. Uguz
reported to be 0.2–0.58 and 3–7%, respectively (Borgatta etal. 1997; Davanzo etal.
2013; Orsolini etal. 2016; Kronenfeld etal. 2017). Adverse events have been rarely
reported (Kronenfeld etal. 2017). Accumulation risk in infants due to the long halflife of diazepam is an important restrictive factor for its usage during the lactation
period. A recently developed scoring system pertaining to the compatibility and
safety of psychotropic drugs during breastfeeding has indicated that diazepam
exhibits a low level of safety and should be employed with caution (Uguz 2021).
Additionally, long-term use by nursing mothers can result in sedation and lethargy
that may lead to severe feeding problems and weight loss in the infants. Therefore,
use of diazepam chronically and/or at high doses should be avoided, and breastfed
infants should be carefully monitored for feeding, weight, and sedation (Iqbal etal.
2002; Orsolini etal. 2016).
13.2.2 Clonazepam
Available data indicate that the use of clonazepam during the lactation period was
about two-fold higher than diazepam (Kronenfeld etal. 2017). Limited available
data suggest that it has similar safety features as diazepam such as a low M/P ratio
(0.33), RID value (2.5%), usually undetectable plasma levels, and a high accumulation risk in the infants (Birnbaum etal. 1999; Rubin etal. 2004; Orsolini etal. 2016;
Kronenfeld etal. 2017). According to available data, clonazepam has been shown to
have low safety prole for breastfeeding women and should be used with caution
(Uguz 2021). On the other hand, a descriptive study based on the French
Pharmacovigilance Database reported that 3.7% (n=5) of drug-induced adverse
reactions via breastfeeding were related to the use of clonazepam (Soussan etal.
2014). Infants exposed to this benzodiazepine should be carefully monitored for
CNS depression, because adverse effects in infants, especially apnea and sedation,
have been reported with this medication (Iqbal etal. 2002; Kronenfeld etal. 2017).
Long-term use of clonazepam is not recommended; usage should be either a single
dose and/or few doses as possible with caution (Uguz 2017).
13.2.3 Alprazolam
There are 24 cases that reported the use of alprazolam in breastfeeding women in
the literature (Oo etal. 1995; Kelly etal. 2012; Rubin etal. 2004; Kronenfeld etal.
2017). Oo etal. (1995) reported that the mean M/P ratio and RID value for alpra-
zolam were 0.36 and 3%, respectively. The authors also noted that infant plasma
levels of this agent were below the detection limits. Although there are some adverse
events reported in infants including CNS depression (Kelly etal. 2012), irritability,
sleep disturbances, sedation, and drowsiness (Rubin etal. 2004; Kronenfeld etal.
2017) in the literature, their incidence is low. According to the ndings of recent
studies, alprazolam has been reported to be moderately safe and appropriate for use
during breastfeeding. Although alprazolam is considered less favorable than
13 Benzodiazepines andZ-Drugs During Lactation
lorazepam, it is more advantageous compared to diazepam and clonazepam during
breastfeeding (Uguz 2021). However, if used long term, the breastfed infant should
be monitored as closely as possible for CNS effects on the infants. It is recommended that usage should be either a single dose and/or as few doses as possible;
however, long-term use and/or high doses are possible with caution (Uguz 2017).
307
13.2.4 Lorazepam
In women experiencing severe anxiety or insomnia who do not exhibit risk factors
for substance abuse, the short-term use of BZDs, such as lorazepam, during breastfeeding constitutes a signicant component of treatment (Thorsness etal. 2018).
Lorazepam is an intermediate-acting benzodiazepine that has the largest reported
data (n=87) in the literature (Kelly etal. 2012; Kronenfeld etal. 2017). M/P ratio
is 0.15–0.26, and the RID value has been reported to be 10% in one patient (Orsolini
etal. 2016; Kronenfeld etal. 2017). It has been shown that lorazepam is excreted
into breast milk in low concentrations (Iqbal etal. 2002). Kelly etal. (2012) reported
no CNS depression in infants of 64 breastfeeding women taking lorazepam.
Lorazepam has been shown to be moderately safe and suitable for use during breastfeeding (Uguz 2021). When it is considered that lorazepam does not have any accumulation problem in the infants and that the exposure via breast milk is not associated
with adverse effects on the infants (Iqbal etal. 2002), lorazepam appears to be most
preferable benzodiazepine in the lactation period. Using this drug in a single dose
and/or in a low dose is acceptable; however, long-term use and/or high doses are
possible with caution (Uguz 2017).
13.2.5 Oxazepam
Half-life of oxazepam in maternal plasma is shorter than alprazolam and lorazepam.
Its passage into breast milk is relatively low as shown by its reported M/P ratio
(0.1–0.3) and RID value (0.7%). Moreover, to date, no adverse effects have been
observed in the infants. However, the availability of safety data from very few cases
in the literature (n=4) is a major issue deterring the prescription of oxazepam during the lactation period (Kronenfeld etal. 2017). For this reason, usage should be
either a single dose and/or as few doses as possible; however, long-term use and/or
high doses are possible with caution. Oxazepam has been reported to have low
safety during breastfeeding and should be used with caution (Uguz 2021).
13.2.6 Midazolam
Although midazolam is one of benzodiazepines that is frequently used during lactation, its usage in patients with psychiatric diagnosis is very rare (Uguz 2017).
Incidence of adverse events in the infants is low. Midazolam has been shown to be
308
safe and suitable for use during the breastfeeding period (Uguz 2021). Other advantages of this drug are a short half-life, being undetectable in the plasma of most
infants, low M/P (0.2) ratio, and RID value (<1%) (Nitsun etal. 2006; Kronenfeld
etal. 2017). Although midazolam may be used as a single dose with caution in
patients with severe agitation, it does not appear to be appropriate for long-term
usage since it is an intravenous anesthetic agent (Nitsun etal. 2006).
B. Bakay and F. Uguz
13.3 Z-Drugs
The Z-drugs including zaleplon, zopiclone, eszopiclone, and zolpidem are dened
as non-benzodiazepine hypnotics and are currently more frequently prescribed
compared to benzodiazepines for the treatment of insomnia (Okun et al. 2015).
Since few studies have suggested their relative safety in breastfed infants, these
agents may be alternative medications to benzodiazepines for the treatment of primary insomnia during lactation (Orsolini etal. 2016).
There is one study with small sample size regarding the use of zaleplon (n=5),
zolpidem (n=5), and zopiclone (n =12) in the literature. Darwish etal. (1999)
reported that M/P ratio for zaleplon was 0.50 and the infant dose was below 1% of
the maternal dose. These data indicate that transfer of zaleplon via breast milk to the
infant was in a very small quantity that was unlikely to be clinically important.
Similarly, the excretion of zolpidem in human milk was reported to be very low
(M/P ratio=0.13) (Pons etal. 1989). The average M/P ratio and weight-adjusted
infant dose for zopiclone were found to be 0.51 and 1.4%, respectively (Matheson
etal. 1990). Zopiclone has a relatively safe prole for use during breastfeeding, and
zaleplon and zolpidem are not appropriate pharmacologic options (Uguz 2021).
However, the clinical effects of these medications on breastfed infants remain
unclear. Therefore, these medications should be used with caution in breastfeeding
women with insomnia.
13.4 Conclusion
The corpus of data in the literature on the safety of psychotropic medications in
breastfed infants does not correlate with the frequency of their usage. The utilization
of BZDs in the treatment of sleep disorders and anxiety symptoms in breastfeeding
mothers is proposed, with the caveat that the safety of this approach is contingent
upon the preference for drugs with the least active metabolite and short half-life
(e.g., lorazepam, oxazepam), with the objective of minimizing the drug’s effects on
the infant (Eleftheriou etal. 2024). Although the available reports do not suggest a
clear contraindication for the use of benzodiazepines, their long-term effects on the
breastfed infants remain unclear. Therefore, decisions concerning these medications
during the lactation period should be made on the basis of the need to treat the
mother and their potential side effects in the infants. Single administration or shortterm usage at low doses seems to be compatible with breastfeeding. The exposed
13 Benzodiazepines andZ-Drugs During Lactation
309
infants should be carefully monitored by the mother and pediatricians during maternal use of benzodiazepines. Short-acting drugs, especially lorazepam, are more
preferable compared to long-acting ones. Limited available data suggest that among
the Z-drugs, zopiclone may be an alternative to benzodiazepines in breastfeeding
women with primary insomnia.
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B. Bakay and F. Uguz
Miscellaneous Drugs During Pregnancy
andLactation
HasanBakay
14.1 Introduction
Drug use during pregnancy and lactation has always posed a challenge for clinicians. Ensuring maternal and infant safety while determining optimal therapy
requires a thorough knowledge of the pharmacokinetic and pharmacodynamic properties of drugs and their potential teratogenic or neonatal effects. Although research
in this area is increasing, there are signicant gaps in the literature, particularly for
drugs that are not routinely included in specic safety categories.
Due to their critical role in opioid substitution therapy, drugs such as methadone and buprenorphine have been studied relatively more extensively during
pregnancy and lactation (Ordean and Tubman-Broeren 2023; Suarez etal. 2022;
Jansson etal. 2024). Similarly, methylphenidate, one of the most commonly
used drugs in the treatment of attention decit hyperactivity disorder (ADHD),
which has a prevalence rate of approximately 3% among women of childbearing
age, is also among the well-studied compounds (Baker etal. 2022; Scoten etal.
2024; di Giacomo etal. 2024). However, data on the use of buspirone and gaba-
pentinoids for the treatment of anxiety disorders, and naltrexone, acamprosate,
baclofen, and disulram for the treatment of alcohol use disorder in this sensitive period are limited (Freeman etal. 2022; Beau etal. 2024; Quintrell etal.
2023). Similarly, there is a signicant gap in the literature regarding the use of
biperiden, a drug that can effectively control the extrapyramidal side effects of
antipsychotic drugs (Escobar-Vidarte etal. 2019). An increase in the incidence
of restless legs syndrome (RLS), which is thought to be related to iron
14
H. Bakay (*)
Department of Psychiatry, Faculty of Medicine, Necmettin Erbakan University,
Konya, Türkiye
e-mail: hasan.bakay@erbakan.edu.tr
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
F. Uguz, L. Orsolini (eds.), Perinatal Psychopharmacology,
https://doi.org/10.1007/978-3-031-99720-4_14
311